Modulators of GTPases and their use

Abstract

The present invention relates to molecules which function as modulators (i.e., inhibitors and agonists) of the Ras-homologous (Rho) family of small GTPases (e.g. Rac, Cdc42 and Rho GTPases) and their use to treat diseases, including cancers (including solid tumors-medulloblastoma, ovarian, breast, head and neck, testicular, prostate among others and hematologic malignancies-B cell lymphoma, where these GTPases are overexpressed or hyperactivated), sporadic and genetic diseases where activation of Rho GTPases plays a pivotal role (Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease and Alzheimer's disease) which are mediated through these proteins. Compounds according to the present invention may also be used as a therapy for the treatment of Entamoeba spp. or Acanthamoeba spp. infections, especially including Entamoeba histolytica.

The invention claimed is: 
     
       1. A method of treating ovarian cancer in a human patient in need thereof, comprising the step of:
 (a) measuring the expression or activity of Rac1 or Cdc42 in a sample of ovarian cancer tissue obtained from the patient; and 
 (b) only if Rac1 or Cdc42 in the sample is overexpressed or activated compared to the expression or activity in non-cancerous tissue, administering to said patient an anti-cancer effective amount of a composition comprising ketorolac, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, additive or excipient, wherein the ketorolac consists an effective amount of R-ketorolac. 
 
     
     
       2. The method of  claim 1 , wherein the R-ketorolac is enantiomerically pure. 
     
     
       3. The method of  claim 1  wherein the ovarian cancer of the patient has increased expression or activity of Rac1. 
     
     
       4. The method of  claim 3  wherein the expression of Rac1 is measured by performing immunohistochemical analysis on the tissue. 
     
     
       5. The method of  claim 3  wherein the expression of Rac1 is measured by measuring Rac1 mRNA using quantitative PCR analysis. 
     
     
       6. The method of  claim 3  wherein the expression of Rac1 is measured by performing a GLISA activity assay for Rac1 GTPase activity. 
     
     
       7. A method to treat ovarian cancer in a patient comprising administering to a patient in need thereof an anti-cancer effective amount of a composition comprising ketorolac, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, additive or excipient, so as to treat said ovarian cancer in the patient
 wherein the ketorolac consists an effective amount of R-ketorolac, and 
 wherein Rac1 or Cdc42 is overexpressed or activated in the patient's ovarian cancer tissue as compared to the expression or activity in non-cancerous tissue. 
 
     
     
       8. The method of  claim 7 , wherein the R-ketorolac is enantiomerically pure.